Lung disease is the major contributor to morbidity and the primary cause of mortality of CF patients. The lung disease is characterized by pulmonary obstruction and tissue damage due to chronic inflammation and opportunistic pathogen colonization. The severity of the CF-associated lung disease, how3ever, is variable, and disease among patients with identical CFTR genotypes, and a higher concordance in monozygotic compared to dizygotic CF twins, suggest the contribution of non-CFTR genetic factors in the disease. Identification of these secondary genetic factors will broaden our understanding of CF disease and possibly led to new treatments. The delineation of the genetic influences on CF lung disease, however, is not feasible through human studies due to environmental variability, genetic heterogeneity and small sample sizes. Mice deficient of CFTR function "CF mice" generally die of intestinal obstruction by the age of 5 weeks without displaying significant lung disease. Amelioration of the intestinal obstructions by weaning onto a liquid diet, however, results in increased lifespan and consequential disclosure of abnormal lung phenotypes. In particularly, congenic C57BL/6J (B6) CF mice, in the absence of pathogens, spontaneously develop signs of inflammatory lung disease, not unlike those seen in CF patients. In contrast, under the same conditions no sign of lung disease is observed in their control subs or other strains of F mice, including the BALB/cJ (Bc) congenic CF animals. The two congenic strains of CF mice thus provide a means to characterize the factors contributing to the CF lung disease as well as map and characterize secondary genetic factors underlying the differences. The proposed study will employ an in-depth physiological characterization of pulmonary milieu neutrophil function, along with controlled breeding experiments and candidate gene and QTL genetic mapping to identify the factors contributing to the differences in lung phenotypes between the B6 and Bc CF mice, and possibly CF patient variability.